Measurement Of anti-Xa Activity Research Articles

Анти-Ха активность у пациентов с неклапанной фибрилляцией предсердий на фоне приема апиксабана и ривароксабана

Direct oral anticoagulants (DOAC) are widely used for prevention of stroke in patients with atrial fibrillation. The need for therapeutic drug monitoring of DOACs remains unclear. Measurement of anti-Xa activity that directly correlates with serum drug concentration seems to be a promising approach for monitoring of Xa inhibitors.

Stability of Rivaroxaban and Apixaban Anti-Xa Activities in Whole Blood Samples: A French Bicentric Study.

Over the last 10 years, the use of direct oral anticoagulants (DOACs) in the management of venous thromboembolism and atrial fibrillation grew significantly, and in particular direct factor Xa inhibitors rivaroxaban and apixaban. Clinical trials of these molecules did not underline the necessity of systematic laboratory monitoring, and the measurement of anti-Xa activity was only indicated in urgent situations such as trauma or prior to acute surgery.[1] [2] [3] [4] However, in 2021, the International Council for Standardization in Haematology (ICSH) updated these recommendations and added several nonurgent indications for anti-Xa activity measurement: advanced age, severe renal failure, ahead of a surgical procedure at high bleeding risk, body mass index >40 kg/m2, and drug interactions.[5] [6] The 2018 ICSH recommendations stated that citrated whole blood samples for anti-Xa activity measurement should be processed within 4 hours of collection, but without providing evidence. Moreover, the French Working Group on Hemostasis and Thrombosis recommendations indicated a shorter stability, of 2 hours, in accordance with the only study then published in the literature.[7] [8] [9] In practice, some laboratories may find it difficult to comply with these short delays.

Monitoring of Unfractionated Heparin Therapy in the Intensive Care Unit Using a Point-of-Care aPTT: A Comparative, Longitudinal Observational Study with Laboratory-Based aPTT and Anti-Xa Activity Measurement.

Continuous intravenous unfractionated heparin (UFH) is administered routinely in the intensive care unit (ICU) for the anticoagulation of patients, and monitoring is performed by the activated partial thromboplastin time (APTT) or anti-Xa activity. However, these strategies are associated with potentially large time intervals before dose adjustments, which could be detrimental to the patient. The aim of the study was to compare a point-of-care (POCT) version of the APTT to (i) laboratory-based APTT and (ii) measurements of anti-Xa activity in terms of correlation, agreement and turnaround time (TAT). Thirty-five ICU patients requiring UFH therapy were prospectively included and followed longitudinally for a maximum duration of 15 days. UFH was administered according to a local adaptation of Raschke and Amanzadeh’s aPTT nomograms. Simultaneous measurements of POCT-APTT (CoaguCheck® aPTT Test, Roche Diagnostics) on a drop of fresh whole blood, laboratory-based APTT (C.K. Prest®, Stago) and anti-Xa activity (STA®Liquid anti-Xa, Stago) were systematically performed two to six times a day. Antithrombin, C-reactive protein, fibrinogen, factor VIII and lupus anticoagulant were measured. The time tracking of sampling and analysis was recorded. The overall correlation between POCT-APTT and laboratory APTT (n = 795 pairs) was strongly positive (rs = 0.77, p < 0.0001), and between POCT-APTT and anti-Xa activity (n = 729 pairs) was weakly positive (rs = 0.46, p < 0.0001). Inter-method agreement (Cohen’s kappa (k)) between POCT and laboratory APTT was 0.27, and between POCT and anti-Xa activity was 0.30. The median TATs from sample collection to the lab delivery of results for lab-APTT and anti-Xa were 50.9 min (interquartile range (IQR), 38.4–69.1) and 66.3 min (IQR, 49.0–91.8), respectively, while the POCT delivered results in less than 5 min (p < 0.0001). Although the use of the POCT-APTT device significantly reduced the time to results, the results obtained were poorly consistent with those obtained by lab-APTT or anti-Xa activity, and therefore it should not be used with the nomograms developed for lab-APTT.

Is specific anti-factor Xa activity measurement a way to predict relevant bleeding in non-valvular atrial fibrillation (NVAF) patients?

Anti-Xa direct oral anticoagulants (DOACs) are first line therapy for stroke prevention in NVAF patients. There is no need of regular anticoagulation monitoring and dose reduction may be indicated in patients showing a high bleeding risk. However, we still estimate 2 to 5% of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) in NVAF patients. Thereupon, we must identify other bleeding risks such as biological overdose. The goal of this study was to investigate specific anti-Xa activity measurement as a mean to predict bleeding complications in NVAF patients. One hundred and forty-six patients (either on apixaban or rivaroxaban) were enrolled from 2017 to 2019. The DOACs measurements were performed the day of inclusion. We determined an overdose and therapeutic underdose thresholds according to expected anti-Xa plasma range levels filled in the European heart rhythm association guide use of DOACs. MB, CRNMB and minor bleedings and strokes occurring during the follow up (up to 3 years) were recorded. We analysed the correlation between therapeutic overdose and the studied endpoints. To this day, the statistical analyses are still being conducted. The first results show that among the 146 patients, more or less 14% were considered overdosed. Moreover, a statistical trend was found between overdosed patients and MB or CRNMB. In routine clinical practice, anti-Xa activity measurement could be used to predict bleeding risk in a selected population in order to adapt doses or to consider a change of molecule.

Evaluation of the anticoagulant effect of low-molecular-weight heparins based on the anti-Xa level during haemodialysis.

Evaluate the relationship between anti-Xa activity and anticoagulant effect, and ascertain whether accumulation of low-molecular-weight heparins (LMWH) occurs during haemodialysis. There was an observational, single-centre study among participants who received the LMWH dalteparin, enoxaparin or nadroparin. A standard haemodialysis session lasted 4 hours. All included participants had anti-Xa activity measures at 0.5 and 4 hours. Extracorporeal circuit (ECC) clotting was evaluated by visual inspection of the haemodialyser and bubble trap after each haemodialysis session. The same person was tested at three consecutive haemodialysis sessions. Overall, 90 participants were enrolled and 259 haemodialysis sessions assessed. There was no significant difference in the mean anti-Xa activity at 0.5 and 4 hours for three consecutive sessions, so LMWH accumulation did not occur. There were 69 (26.6%) sessions in which, ECC clotting was visible. Compared with the group where circuit clotting did not occur, the LMWH dose and anti-Xa activity in the group where circuit clotting occurred were significantly lower. At 0.5 hour, anti-Xa <0.88 IU/mL had significantly higher odds of ECC clotting than that at ≥0.88 IU/mL. At 4 hours, anti-Xa <0.35 IU/mL had significantly higher odds of ECC clotting than that at ≥0.35 IU/mL. We found that over three haemodialysis sessions, no significant accumulation of LMWH was evident in subjects receiving a LMWH dose of between 2000 and 5000 IU for regular. Anti-Xa activity measurement can be used to adjust the dosage of LMWH and predict the anticoagulant effect during haemodialysis.

Monitoring Unfractionated Heparin Treatments. Stability of Plasma Anti-Xa Activity up to 4 Hours in Citrated Tubes

Background: Unfractionated heparin (UFH) has been in clinical use for more than half a century. Monitoring UFH treatments is mandatory due to large inter- and intra-individual variations in its anticoagulant activity, with a risk of thrombosis in case of under-dosing and a risk of hemorrhage in case of over-dosing. Laboratory monitoring of UFH treatments is usually based on the prolongation of activated partial thromboplastin time (aPTT), or on the measurement of plasma anti-Xa activity. As UFH present in the patient's blood sample could be neutralized by platelet factor 4 (PF4) released by in-vitro activated platelets, it is recommended to perform the tests aimed at evaluating its anticoagulant activity as soon as possible after blood collection. Actually, the current guidelines recommend a maximum delay of 2 hours between blood sampling and testing for anti-Xa activity or aPTT prescribed for monitoring treatments by UFH, when blood is collected into citrated tubes. As such a short delay could be an issue, particularly for multisite centres, we evaluated the potential impact of a longer delay on test results. Design of the study: For that purpose, 2 citrated evacuated tubes containing 0.109 M tri-Na citrate (1 vol./9 vol.) were collected from patients on UFH: one was centrifuged and tested within 1h after blood collection (T1h) and one was stored for 4h at room temperature (+22°C) before being centrifuged and immediately analyzed (T4h). Methods: Anti-Xa activity was evaluated using 2 reagents: Biophen Heparin LRT (Hyphen Biomed, Neuville-sur-Oise, France) and HemosIL Liquid Heparin (Instrumentation Laboratory, IL, Bedford, MA, USA). aPTT was evaluated using the HemosIL SynthASil reagent (IL). All assays were automated on an ACL TOP 700 CTS (IL). As the distributions of the data were not found to be normal, anti-Xa and aPTT results were expressed as the median values (with ranges), and comparison of test results obtained at T1h and T4h performed using the Wilcoxon test. Test results were also compared according to Bland-Altman. Results: A total of 123 paired tubes were investigated. Analytical comparison of anti-Xa activity demonstrated a significant decrease (p&lt;0.0001) after a 4 h-storage at room temperature (T4h) vs. a &lt;1h-delay (T1h), for the two evaluated reagents (Table). The mean bias between test results obtained at T4h and T1h, evaluated according to Bland and Altman, was &lt;0.05 IU/mL (in absolute value) for the two reagents, and identical for anti-Xa activities below or above 0.50 IU/mL. Such a value was below the imprecision of the techniques. There were 12 cases of discrepancy as whether test results were within the therapeutic range (0.30 - 0.70 IU/mL) or not when evaluated at T4h vs. T1h using the Hyphen reagent (9.8%), and 12.9% with the IL reagent. In most cases, these discrepancies were found for anti-Xa activities close to the lower limit of the therapeutic range, and would not have induced any change in the management of anticoagulation in these patients. APTT was significantly shortened (p&lt;0.0001) after a 4h- vs. a 1h-storage at room temperature, with a mean bias of -8.1 sec, corresponding to a -0.25 decrease in ratio [relative change of -12.1% (95%CI= -34.8 +10.6)]. If considering the aPTT therapeutic range corresponding to anti-Xa activity between 0.30 and 0.70 IU/ml, 29 cases of discordant test results (23.6%) were observed that could have induced changes in the management of anticoagulation in 10% of the patients. Finally, the concordance whether test results measured at T4h and T0 were within or outside the therapeutic range was excellent for anti-Xa activity (kappa=0.813) and good for aPTT (kappa=0.661). Conclusions: These results suggest that extending to 4h the delay between blood sampling and measurement of anti-Xa activity prescribed for monitoring UFH treatments when blood is collected into citrated tubes is acceptable and safe, at least when evaluated with the two tested reagents. As change in aPTT results was found to be of a greater order of magnitude and more relevant, it could be justified recommending a shorter delay. Table Disclosures No relevant conflicts of interest to declare.

Monitoring of heparins in antithrombin-deficient patients

IntroductionHeparins exert their anticoagulant effect through activation of antithrombin. Whether antithrombin deficiency leads to clinically relevantly reduced anti-Xa activity of heparins is unknown. We investigated the relation between antithrombin deficiency and anti-Xa activity measurements of plasma samples spiked with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Materials and methodsPlasma samples from 34 antithrombin-deficient subjects and 17 family controls were spiked with UFH and LMWH (nadroparin) aimed to correspond with an anti-Xa activity of 0.8 IU/mL. Antithrombin, β-antithrombin and anti-Xa activities were measured. ResultsMean anti-Xa activity with LWMH was 0.55 IU/mL (0.30–0.74) (recovery 69%, 38–93%) in antithrombin-deficient subjects and 0.82 (0.71–0.89) IU/mL in controls (recovery 103%, 89–111%). Expected anti-Xa measurements after LMWH spiking were found in 17/17 non-deficient subjects and in 8/34 antithrombin-deficient subjects. Anti-Xa measurements in the expected range (0.6–1.0 IU/mL) after UFH spiking were found in 17/17 non-deficient subjects and in 1/22 antithrombin-deficient subjects. Antithrombin activity correlated with anti-Xa activity of UFH (R = 0.77) and LMWH (R = 0.66). Mixing studies of pooled normal plasma and antithrombin-deficient plasma showed that anti-Xa recovery was linearly reduced with antithrombin activity decreasing below 100%. ConclusionsReduced antithrombin activity causes significantly reduced anti-Xa levels. Standard LWMH- or UFH-doses are likely to lead to under treatment in antithrombin-deficient individuals.

Practical Value of Anti-Xa Activity in the Evaluation of Extracorporeal Circuit Anticoagulation during Haemodialysis: Results of a Cross-Sectional Single-Centre Study

Background/Aims: Anticoagulation of the extracorporeal circuit is essential for adequate haemodialysis (HD). Low molecular weight heparins (LMWHs) are safe and sufficient towards achieving this goal. In the Netherlands, dosage is based on bodyweight and adjusted based on clinical events. LMWH levels during dialysis can be quantified through measurement of the anti-Xa activity and a target range of 0.5-1.0 IU/mL has been proposed. We aimed to evaluate the practical value of the anti-Xa activity to guide LMWH dosage in HD patients. Additionally, the value of the activated partial thromboplastin time (APTT) was investigated. Methods: All prevalent adult HD patients of our dialysis clinic were included. APTT and anti-Xa activity were measured before, during and after 2 dialysis sessions. Clinical and dialysis characteristics, including LMWH dosage, were derived from digital patient charts. Results: Our final study cohort consisted of 83 patients. LMWH dosage during dialysis was appropriate for bodyweight in 61% of cases, of which 50% reached an anti-Xa activity within the putative target range of 0.5-1.0 IU/mL. Forty-six percent of patients had an anti-Xa activity >1.0 IU/mL. Anti-Xa levels during and after dialysis were significantly correlated (r = 0.803, p < 0.01). No thrombotic or haemorrhagic complications were observed in this study. Correlation of APTT with anti-Xa activity was poor. Conclusion: Anti-Xa activity measurements during dialysis can identify patients in whom LMWH dosage should be lowered in a subsequent dialysis session. Whether such an intervention leads to a decrease in haemorrhagic complications needs to be evaluated in prospective studies.

Adjusted value of thromboprophylaxis in hospitalized obese patients: A comparative study of two regimens of enoxaparin: The ITOHENOX study

Thromboprophylaxis is a mainstay of hospital care in patients at high risk of thrombosis. Fixed doses of low-molecular-weight heparin (LMWH) are recommended for thromboprophylaxis in patients admitted to hospital for an acute medical condition. However, the distribution of LMWH is weight-based, and the efficacy of standard doses in obese patients may be decreased. Data for obese patients are mainly available in bariatric surgery with extremely obese patients who are at greater risk of venous thromboembolism than those hospitalized for a medical condition. We conducted a randomized control trial in medically obese inpatients (BMI≥30kg/m2) assessing two regimens of enoxaparin (40mg and 60mg SQ daily) in order to determine whether a stronger dosage would achieve higher anti-Xa level suitable for thromboprophylaxis. Between September 2013 and April 2015, 91 patients were included in the study (mean (±standard deviation) age was 70.4±10.7years, average BMI 37.8±6.4kg/m2). Main indications of thromboprophylaxis were mainly acute infection (50%), acute respiratory failure (10%), acute congestive heart failure (9%) and acute rheumatic disorders (18%).Average anti-Xa activity, measured 4h after the third administration of enoxaparin was 0.25±0.09IU/mL in group 1 (enoxaparin 40mg) and 0.35±0.13IU/mL in group 2 (enoxaparin 60mg) (P<10−3). The proportions of patients with normal anti-Xa activity (between 0.32 and 0.54IU/mL) were 31% (n=11) and 69% (n=24) in group 1 and 2 respectively (P=0.007). The proportions of anti-Xa activity measurement below the normal range were 64% and 36% in group 1 and 2 (P<10−3) respectively. Subgroup analysis focusing on high weight patients (above 100kg, n=45) showed a marked difference in the proportion of patients with normal anti-Xa activity between group 1 (9%) and 2 (44%) (P=0.009). No venous thromboembolism occurred during the study and one patient in group 1 died because of hemorrhagic shock due to a gastric ulcer. Incidence of adverse events was not different between the two groups (P=0.52).In conclusion, the ITOHENOX study shows in medically obese inpatients that thromboprophylaxis with enoxaparin 60mg provides higher control of anti-Xa activity, without more bleeding complications than the standard enoxaparin regimen. This trial is registered with ClinicalTrials.gov, number NCT01707732.

Evaluation of Factor Xa-Specific Chromogenic Substrate Assays and the Determination of Pharmacokinetics of Fondaparinux

Fondaparinux (FPX), a synthesized factor Xa inhibitor, is one of the most popular anticoagulants for the prevention of postoperative venous thromboembolism (VTE). Although routine monitoring is not required, the bleeding adverse events cannot be neglected, and the measurement of anti-Xa activity is expected to be monitored. The primary purpose of this study is to evaluate the performances of 2 chromogenic assays for the detection of anti-Xa activity. Furthermore, the pharmacokinetics of FPX was examined using chromogenic assays. Anti-Xa activity was measured using 2 FPX-based chromogenic substrates (S2222 and STA-Liquid Anti-Xa). The reproducibility, detection limits, linearity, and correlations between the substrates were examined using normal plasma doped with low and high concentrations of FPX formulation. In addition, anti-Xa activity in 235 clinical samples from 164 cases treated was measured, and the pharmacokinetics of FPX was evaluated. Both of the tested substrates were capable of accurately measuring the anti-Xa activity of FPX, with a lower limit of 0.05 μg/mL and a coefficient of variation of less than 10%. The repeated administration of FPX induced a gradual but significant increase in the anti-Xa activity, which was negatively correlated with body weight and estimated glomerular filtration rate. No significant correlation between the anti-Xa activity and the occurrence of postoperative VTE or bleeding event was observed. Anti-Xa activity can be successfully determined using 2 chromogenic assays and automated biochemical analyzers. The clinical significance of anti-Xa activity monitoring should be examined in the future study.

Heparin-Calibrated Chromogenic Anti-Xa Activity Measurements in Patients Receiving Rivaroxaban: Can This Test Be Used to Quantify Drug Level?

Determination of plasma rivaroxaban concentration may be necessary in certain clinical situations. Rivaroxaban concentration can be accurately and rapidly determined using a chromogenic anti-activated factor X (factor Xa) assay with specific drug calibrator material. However, there are currently no Food and Drug Administration (FDA)-approved rivaroxaban calibrators available in the United States. To determine whether FDA-approved commercial kits for measuring heparin anti-factor Xa activity can be used to assess rivaroxaban concentrations when calibrated for unfractionated heparin or low-molecular-weight heparins. Trough and peak samples were taken from 30 patients taking rivaroxaban as part of their routine care for atrial fibrillation or venous thromboembolism. The samples were tested using 3 different FDA-approved commercial kits for measuring heparin anti-factor Xa activity. There was acceptable correlation between rivaroxaban levels and heparin anti-factor Xa activity using Berichrom and COAMATIC heparin kits. The STA liquid heparin method was the most sensitive to presence of rivaroxaban. This study demonstrates a strong correlation, but variability between kits, for assessing rivaroxaban concentrations using heparin anti-factor Xa assays. The extent of the heparin calibration curve significantly limits the measurable rivaroxaban range, and this application may be useful only for trough samples. The STA liquid heparin, being exquisitely sensitive to rivaroxaban, may be suitable for ruling out presence of the drug. The routine use of heparin-calibrated anti-factor Xa assays to quantify rivaroxaban is not advocated, and when applied, it must be used with caution and limitations clearly understood.

Effects of factor VIII levels on the APTT and anti-Xa activity under a therapeutic dose of heparin.

In pregnant women, activated partial thromboplastin time (APTT) does not precisely reflect the anticoagulant effect of a therapeutic dose of heparin. However, the measurement of anti-Xa activity can be used to monitor the anticoagulant effect of heparin, since the plasma concentrations of coagulation factors increase in pregnant women. We evaluated the in vitro effects of increased concentrations of fibrinogen and other coagulation factors (FVII, FVIII, and FIX) on the results of assays of APTT and anti-Xa activity in plasma samples with various therapeutic concentrations of unfractionated heparin (UFH). In the presence of UFH, APTT was shortened by increased concentrations of fibrinogen, FVII, or FVIII, and this effect was much stronger when the FVIII concentration was increased. In the plasma samples containing 0.5 or 0.7 U/mL of UFH, the APTT was shortened by approximately half or one-third, respectively, when 6UFVIII/mL was added to the sample. The anti-Xa activity was not influenced by increased concentrations of the coagulation factors. In the present study, we also evaluated the sensitivities to UHF of four APTT reagents, and found a 1.65-fold difference in the sensitivity to UFH among APTT reagents. Our results demonstrate that increased FVIII concentration shortens APTT under therapeutic doses of UFH, and that APTT thus underestimates the anticoagulant effect of UFH in pregnant women, mainly due to the increased FVIII concentration.

Low-molecular-weight heparin pharmacokinetics: a dual absorption model approach

The aim of this study was to develop a novel population pharmacokinetic (PPK) model of dalteparin after subcutaneous (s.c.) injection, to describe the impact of the "flip-flop" phenomenon and to demonstrate any ethnic difference between Asian and Caucasian subjects. The PPK model was constructed based on data collected from Asian (Japanese) and Caucasian (French) subjects with a total of 931 plasma anti-Xa activity measurements. After s.c. injection, the apparent elimination half-life of the dalteparin was about 4 hours, longer than that reported after intravenous (i.v.) injection, indicating a "flip-flop" phenomenon. In addition, following the mono-exponential decline profile after s.c. injection, a longer secondary phase was apparently observed in 70% of subjects. To investigate the phenomenon, we applied a dual absorption model including fast first-order and slow zero-order inputs as the structural model. The PPK model for s.c. injection provided the half-life consistent with that of i.v. injection and could account for the observed bi-phasic profile. Body weight and gender for clearance and body weight for volume of distribution were identified as covariates. Due to lower body weight in Asian subjects, an ethnic difference might occur but it would not be reflected by per kg body weight injection. Dalteparin PK profiles after s.c. injection were described reasonably by the novel PPK model based on flip-flop pharmacokinetics and a dual absorption process.

Monitoring of unfractionated heparin with rotational thrombelastometry using the prothrombinase-induced clotting time reagent (PiCT®)

PurposeTo achieve sufficient and safe anticoagulation with unfractionated heparin (UFH) a close and reliable drug monitoring is necessary. In general, the activated partial thromboplastin time (APTT) is used for this purpose. In acute phase response, however, the APTT test procedure might be unreliable e.g. with false low results in the presence of elevated factor VIII. In this so called heparin resistance, measurement of anti-Xa activity is recommended over APTT to avoid potentially harmful dose escalation. A combination of anti-Xa measurement and global hemostatic testing with ROTEM® employing the anti-Xa sensitive PiCT® reagent showed high correlation with enoxaparin levels. This test modification could also be suitable for monitoring UFH.Aim of the study was to evaluate the correlation between PiCT®-ROTEM® and levels of UFH. MethodsIn this in-vitro study blood samples from healthy volunteers were spiked with UFH and subjected to different ROTEM® tests. ResultsThere was a linear correlation between UFH level and clotting time (CT) in the PiCT®-ROTEM® test with an excellent correlation coefficient of 0.92. Additional endpoints showed similar results (PiCT®-ROTEM® MaxVel r=−0.85 and PiCT®-ROTEM® t_MaxVel r=0.88). ConclusionsAs a point-of-care applicable tool ROTEM® is immediately at hand. If further clinical studies confirm sensitivity in heparin resistance, PiCT®-ROTEM® could permit rapid UFH dose adjustments especially required in critical illness with acute phase response.

Les résistances aux traitements curatifs par l’héparine non fractionnée

Unfractionated heparin has been used as antithrombotic therapy for many years. Its main effect is attributed to the activation of antithrombin (AT), the heparin/AT complex inactivating both factor IIa (thrombin) and factor Xa. Resistance to unfractionated heparin with clinical or biological expression is uncommon. The occurrence of venous or arterial thrombosis or the extension of thrombosis in a patient receiving unfractionated heparin, should always raise suspicion of either AT deficiency or type 2 heparin-induced thrombocytopenia (HIT type 2). HIT type 2 is not a true heparin resistance but an immune complication that requires heparin discontinuation and the use of alternative anticoagulants. Biological heparin resistance is suspected in the presence of a normal or not prolonged activated partial thromboplastin time despite the administration of increasing dose of heparin. Measurement of anti-Xa activity is useful to adjust heparin treatment. Isolated biological heparin resistance is encountered in several physiological and pathological situations including inflammatory and infectious disorders, pregnancy and thrombocytosis. It also occurs in acquired antithrombin deficiency of nephrotic syndrome, l-asparaginase treatment or cardiopulmonary bypass. Biological heparin resistance is relatively common, but clinically significant resistance to heparin is rare and should always raise suspicion of either AT deficiency or type 2 heparin-induced thrombocytopenia.

Surveillance des traitements anticoagulants chez les patients atteints de cancer

Venous thromboembolic events are frequent in patients with cancer. Patients on anticoagulant therapy are both at increased risk for subsequent thromboembolic and bleeding events. Whatever the therapeutic option (vitamin K antagonists [VKA] or low-molecular-weight heparin [LMWH]) a clinic and biological monitoring is required. International Normalized Ratio (INR) variability is increased in patients with cancer as compared with patients without cancer and should be maintained in the target range. Anti-Xa activity measurement may be used in LMWH treatments, in order to detect a possible accumulation in any patients; platelet count monitoring is recommended. Interpretation is most often difficult because of numerous possible causes of thrombopenia in the patient with cancer. Anticoagulant clinics are developed in order to help practitioners and participate in the monitoring of anticoagulant treatments in those patients.

Monitoring of unfractionated heparin with the activated partial thromboplastin time: determination of therapeutic ranges

The purpose of the present study was to determine therapeutic ranges for unfractionated heparin therapy using the activated partial thromboplastin time (APTT) by calibration against anti-Xa concentration. APTT assays were performed locally, i.e. at the institution of blood collection, on fresh plasma samples from patients treated with intravenous unfractionated heparin. The measurements were performed by 25 Dutch clinical laboratories using 11 different APTT reagents and 10 different types of coagulometers. After the local APTT measurement, the samples were frozen and transported to a central laboratory for measurement of anti-Xa activity. The number of samples from the participating laboratories ranged from 10 to 48. Local APTT results were correlated with the central anti-Xa measurements. Orthogonal regression analysis of log-transformed values was used to calculate APTT therapeutic ranges corresponding to anti-Xa concentrations of 0.29–0.47 IU/ml. The calculated APTT ranges were different between laboratories, even when the same reagent was used. In many laboratories, the therapeutic APTT range in use was much wider than the calculated range. Imprecision of the calculated APTT range was influenced by the wide scatter of the measurement points and by the selection of samples for the orthogonal regression equation. The present results show that, if anti-Xa concentrations of 0.29–0.47 IU/ml reflect the true therapeutic range, many laboratories do not use the proper therapeutic APTT range.

Influence of patient characteristics and renal function on factor Xa inhibition pharmacokinetics and pharmacodynamics after enoxaparin administration in non-ST-segment elevation acute coronary syndromes

Background The current standard of care for patients with non-ST-segment elevation acute coronary syndromes (ACS) includes antithrombotic therapy with aspirin and heparin. Although emerging data suggest that low-molecular weight preparations offer distinct advantages over unfractionated heparin, limited information on patient-related factors that may influence dosing, safety, and efficacy is available. Purpose The purpose of our study was the determination of the impact of patient age, sex, body weight, and renal function on factor Xa inhibition pharmacokinetics and pharmacodynamics after enoxaparin administration in patients with ACS. Methods and Results Patients enrolled in the TIMI 11A trial received a full complement of antiischemic therapy, aspirin, and enoxaparin (30 mg intravenously, followed by weight-adjusted doses of either 1 mg/kg or 1.25 mg/kg subcutaneously every 12 hours). Before and after the third and last doses, blood samples were obtained from 445 patients for measurement of anti-Xa activity. The mean apparent clearance, distribution volume, and plasma half-life were 0.733 L/h, 5.24 L, and 5 hours, respectively. Among a wide range of clinical and laboratory covariates, creatinine clearance emerged as the most influential factor on apparent clearance, area under the curve, and anti-Xa activity. Patients with marked renal impairment (creatinine clearance <40 mL/min) had higher trough and peak anti-Xa activity compared with those with normal renal function and were more likely to have major hemorrhagic events. Conclusion The pharmacokinetic and pharmacodynamic profiles after enoxaparin administration are consistent across a broad range of patients with ACS. Dose adjustments or anti-Xa coagulation monitoring or both will be necessary rarely in routine clinical practice, with the exception of patients with severe renal insufficiency. (Am Heart J 2002;143:753-9.)

A PROSPECTIVE RANDOMIZED STUDY TO COMPARE THE ANTI-XA ACTIVITY AND BLEEDING COMPLICATIONS OF STANDARD AND REDUCED DOSAGE OF FRAXIPARINE FOR THE PROPHYLAXIS OF POSTOPERATIVE DEEP VEIN THROMBOSIS IN RECTAL CANCER SURGERY

Background & Objective: Patients undergoing elective rectal cancer surgery are usually given Fraxiparine based on recommended dosages from Caucasians’ studies (0.2 ml if body weight <50 kg and 0.3 ml if body weight >50 kg) as prophylaxis for deep vein thrombosis (DVT). In our Chinese population, however, a number of cases of severe bleeding complications were observed with this standard dosage regimen. A prospective randomized study was therefore conducted to compare the anti-Xa activity and bleeding complications of this standard regimen and a reduced dosage regimen (0.1 ml if body weight < 50 kg and 0.2 ml if body weight > 50 kg). Methods: 29 patients with rectal cancer (standard : reduced = 14 : 15) were included in this study. Fraxiparine was given 4 hours prior to surgery and blood was taken just before surgery for measurement of anti-Xa activity. Postoperatively the patients were examined clinically for DVT. Perioperative blood loss, transfusion requirements and postoperative bleeding complications were also recorded and analyzed prospectively. Results: The mean anti-Xa activity was significantly higher in the standard dosage group (0.302 u/ml vs 0.219 u/ml, P = 0.029). There was no clinically overt DVT in the two groups. Total perioperative blood loss and transfusion requirements were not different in both groups. However, one patient in the standard dosage group has developed major intraoperative bleeding that necessitated packing and relaparotomy for haemostatsis. This patient finally died of disseminated intravascular coagulopathy. Gross haematuria was also observed in two patients in the standard dosage group. None of the patients in the reduced dosage group had developed any major or minor bleeding complications postoperatively. Conclusion: Fraxiparine as DVT prophylaxis in the Chinese population should be administered at a reduced dosage because it is shown in this study to be as effective as the standard dosage regimen in preventing DVT and yet it is associated with fewer bleeding complications.

Prophylaxis and treatment of thromboembolic diseases during pregnancy with dalteparin

Objectives: To determine if a prophylactic dose of dalteparin, 5000 IU daily, and if the adjusted-weight dalteparin therapeutic dose of 100 IU/kg twice daily are appropriate in pregnancy. Method: Anti-Xa activity levels were used to assess prophylactic (33 women) and therapeutic (15 women) dalteparin dosage throughout pregnancy. Analysis of variance was used and P-values less than 0.05 were considered statistically significant. Results: In the prophylactic group, anti-Xa activity levels did not vary significantly throughout pregnancy ( P=0.15). The initial dalteparin dose was modified on the first anti-Xa activity measurement in eight women, whose weight was statistically different from those remaining on the initial dose ( P<0.001). The adjusted-weight therapeutic dalteparin dose induced adequate anti-Xa activity levels. Conclusions: Dalteparin, 5000 IU daily, is suitable for most pregnant women and does not need to be modified in the third trimester. A therapeutic dalteparin dose adjusted according to pregnancy weight is appropriate.